Clonal Hematopoiesis and Cardiovascular Disease in Patients With Multiple Myeloma Undergoing Hematopoietic Cell Transplant.

Importance: There is a paucity of information on the association between clonal hematopoiesis of indeterminate potential (CHIP) and cardiovascular disease (CVD) in patients with cancer, including those with multiple myeloma (MM) undergoing hematopoietic cell transplant (HCT), a population at high risk of developing CVD after HCT. Objective: To examine the association between CHIP and CVD in patients with MM and to describe modifiers of CVD risk among those with CHIP. Design, Setting, and Participants: This was a retrospective cohort study of patients with MM who underwent HCT between 2010 and 2016 at City of Hope Comprehensive Cancer Center in Duarte, California, and had pre-HCT mobilized peripheral blood stem cell (PBSC) products cryopreserved and accessible for CHIP analyses. The study team performed targeted panel DNA sequencing to detect the presence of CHIP (variant allele frequency 2% or more). Main Outcomes and Measures: The primary end point was the 5-year cumulative incidence and risk for developing de novo CVD (heart failure, coronary artery disease, or stroke) after HCT. Results: Of 1036 consecutive patients with MM (580 male [56%]; median age, 60.0 years) who underwent a first autologous HCT, 201 patients had at least 1 CHIP variant (19.4%) and 35 patients had 2 or more variants (3.4%). The 5-year incidence of CVD was significantly higher in patients with CHIP (21.1% vs 8.4%; P < .001) compared with those without CHIP; the 5-year incidence among those with 2 or more variants was 25.6%. In the multivariable model, CHIP was associated with increased risk of CVD (hazard ratio [HR], 2.72; 95% CI, 1.70-4.39), as well as of individual outcomes of interest, including heart failure (HR, 4.02; 95% CI, 2.32-6.98), coronary artery disease (HR, 2.22; 95% CI, 1.06-4.63), and stroke (HR, 3.02; 95% CI, 1.07-8.52). Patients who had both CHIP and preexisting hypertension or dyslipidemia were at nearly 7-fold and 4-fold increased risk of CVD, respectively (reference: no CHIP, no hypertension, or dyslipidemia). Conclusion and Relevance: CHIP was significantly and independently associated with risk of CVD in patients with MM undergoing HCT and may serve as a novel biologically plausible biomarker for CVD in this cohort. Patients with MM and both CHIP and cardiovascular risk factors had an exceptionally high risk of CVD. Additional studies are warranted to determine if cardiovascular preventive measures can reduce CHIP-associated CVD risk.

Identifying monoclonal gammopathy of undetermined significance from electronic health records.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Use of electronic health records may facilitate large-scale epidemiologic research to elucidate risk factors for the progression of MGUS to MM or other lymphoid malignancies. AIMS: We evaluated the accuracy of an electronic health records-based approach for identifying clinically diagnosed MGUS cases for inclusion in studies of patient outcomes/ progression risk. METHODS AND RESULTS: Data were retrieved from Kaiser Permanente Southern California's comprehensive electronic health records, which contain documentation of all outpatient and inpatient visits, laboratory tests, diagnosis codes and a cancer registry. We ascertained potential MGUS cases diagnosed between 2008 and 2014 using the presence of an MGUS ICD-9 diagnosis code (273.1). We initially excluded those diagnosed with MM within 6 months after MGUS diagnosis, then subsequently those with any lymphoid malignancy diagnosis from 2007 to 2014. We reviewed medical charts for 100 randomly selected potential cases for evidence of a physician diagnosis of MGUS, which served as our gold standard for case confirmation. To assess sensitivity, we also investigated the presence of the ICD-9 code in the records of 40 randomly selected and chart review-confirmed MGUS cases among patients with a laboratory report of elevated circulating monoclonal (M-) protein (a key test for MGUS diagnosis) and no subsequent lymphoid malignancy (as described above). The positive predictive value (PPV) for the ICD-9 code was 98%. All MGUS cases confirmed by chart review also had confirmatory laboratory test results. Of the confirmed cases first identified via M-protein test results, 88% also had the ICD-9 diagnosis code. CONCLUSION: The diagnosis code-based approach has excellent PPV and likely high sensitivity for detecting clinically diagnosed MGUS. The generalizability of this approach outside an integrated healthcare system warrants further evaluation.

Iron chelators induce autophagic cell death in multiple myeloma cells.

We examined the antineoplastic effects of the iron chelators, deferasirox and deferoxamine in multiple myeloma cell lines as well as primary myeloma cells. These iron chelators showed marked antiproliferative activity as well as cytotoxicity toward myeloma cell lines and deferasirox was cytotoxic to bone marrow plasma cells from myeloma patients. We also demonstrate that autophagy induced by iron deprivation is the dominant mechanism that mediates the cytotoxicity of iron chelators in multiple myeloma. Exposure to iron chelators led to repression of mTOR signaling as evidenced by decreased phosphorylation of its target p70S6 kinase. Iron chelation, in particular with deferasirox has the potential to be readily translated to a clinical trial for multiple myeloma.

Use of radioimmunotherapy in stem cell transplantation and posttransplantation: focus on yttrium 90 ibritumomab tiuxetan.

Although autologous stem cell transplantation (ASCT) produces prolonged disease-free survival in many patients with non-Hodgkin's lymphoma (NHL), relapse remains the most common cause of treatment failure. Because of the potential benefit of adding targeted irradiation to conditioning regimens, clinical trials are testing the safety and efficacy of combining radioimmunotherapy with yttrium 90 ibritumomab tiuxetan or iodine 131 tositumomab and chemotherapy, either as replacement for total body irradiation or in addition to standard high-dose chemotherapy (HDC) regimens. Current strategies include using standard or escalated doses of radioimmunoconjugates with HDC before ASCT in patients with relapsed or refractory B-cell NHL. We reviewed the safety and efficacy of (90)Y ibritumomab tiuxetan as part of the conditioning regimen before ASCT. Preliminary data from phase 1 and 2 trials show that (90)Y ibritumomab tiuxetan may be safely added to HDC preparative regimens for high-risk B-cell NHL. Additionally, comparisons of outcomes with radioimmunotherapy and ASCT with historical controls suggest that it may be more effective than conventional regimens. Results of (90)Y ibritumomab tiuxetan alone posttransplantation in select patients who have relapsed after HDC and ASCT are also encouraging. Studies of (90)Y ibritumomab tiuxetan in the setting of allogeneic stem cell transplantation appear promising as well.

Does follicularity in large cell lymphoma predict outcome after autologous stem cell transplantation?

The purpose of this study was to evaluate whether follicular histology in large cell lymphoma influences treatment outcomes after autologous stem cell transplantation (ASCT). It remains an area of controversy whether the natural history of follicular large cell lymphoma (FLCL) is akin to diffuse large cell lymphoma (DLCL) with curative potential or is more similar to indolent follicular lymphomas with a pattern of late relapses after intensive chemotherapy. Although ASCT is a potentially curative treatment for patients with recurrent DLCL, the effectiveness of this approach in patients with FLCL is unclear. We undertook a retrospective analysis of 332 patients with large cell lymphoma who underwent ASCT at the City of Hope Comprehensive Cancer Center. With a median follow-up of 31 months, the projected 10-year overall survival and disease-free survival were similar between patients with FLCL and DLCL. Analysis of prognostic factors demonstrated that although age, chemotherapy refractoriness, and disease status at the time of ASCT were predictive of overall survival/disease-free survival, follicularity did not influence the outcome. Furthermore, the similar plateau in the survival curve for the DLCL and FLCL patients suggests that the behavior of FLCL is similar to that of DLCL and that FLCL is potentially curable with ASCT.